Publications by authors named "Yusuke Kimura"

133 Publications

Nodal-based radiomics analysis for identifying cervical lymph node metastasis at levels I and II in patients with oral squamous cell carcinoma using contrast-enhanced computed tomography.

Eur Radiol 2021 Mar 31. Epub 2021 Mar 31.

Department of Radiology, Graduate School of Medical Science, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.

Objective: Discriminating metastatic from benign cervical lymph nodes (LNs) in oral squamous cell carcinoma (OSCC) patients using pretreatment computed tomography (CT) has been controversial. This study aimed to investigate whether CT-based texture analysis with machine learning can accurately identify cervical lymph node metastasis in OSCC patients.

Methods: Twenty-three patients (with 201 cervical LNs [150 benign, 51 metastatic] at levels I-V) who underwent preoperative contrast-enhanced CT and subsequent cervical neck dissection were enrolled. Histopathologically proven LNs were randomly divided into the training cohort (70%; n = 141, at levels I-V) and validation cohort (30%; n = 60, at level I/II). Twenty-five texture features and the nodal size of targeted LNs were analyzed on the CT scans. The nodal-based sensitivities, specificities, diagnostic accuracy rates, and the area under the curves (AUCs) of the receiver operating characteristic curves of combined features using a support vector machine (SVM) at levels I/II, I, and II were evaluated and compared with two radiologists and a dentist (readers).

Results: In the validation cohort, the AUCs (0.820 at level I/II, 0.820 at level I, and 0.930 at level II, respectively) of the radiomics approach were superior to three readers (0.798-0.816, 0.773-0.798, and 0.825-0.865, respectively). The best models were more specific at levels I/II and I and accurate at each level than each of the readers (p < .05).

Conclusions: Machine learning-based analysis with contrast-enhanced CT can be used to noninvasively differentiate between benign and metastatic cervical LNs in OSCC patients.

Key Points: • The best algorithm in the validation cohort can noninvasively differentiate between benign and metastatic cervical LNs at levels I/II, I, and II. • The AUCs of the model at each level were superior to those of multireaders. • Significant differences in the specificities at level I/II and I and diagnostic accuracy rates at each level between the model and multireaders were found.
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http://dx.doi.org/10.1007/s00330-021-07758-4DOI Listing
March 2021

Development of membrane-insertable lipid scrambling peptides: A time-resolved small-angle neutron scattering study.

Struct Dyn 2021 Mar 19;8(2):024301. Epub 2021 Mar 19.

Department of Biointerface Chemistry, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

Phospholipid transbilayer movement (flip-flop) in the plasma membrane is regulated by membrane proteins to maintain cell homeostasis and interact with other cells. The promotion of flip-flop by phospholipid scramblases causes the loss of membrane lipid asymmetry, which is involved in apoptosis, blood coagulation, and viral infection. Therefore, compounds that can artificially control flip-flop in the plasma membrane are of biological and medical interest. Here, we have developed lipid scrambling transmembrane peptides that can be inserted into the membrane. Time-resolved small-angle neutron scattering measurements revealed that the addition of peptides containing a glutamine residue at the center of the hydrophobic sequence to lipid vesicles induces the flip-flop of 1-palmitoyl-2-oleoyl--glycero-3-phosphocholine. Peptides without the glutamine residue had no effect on the flip-flop. Because the glutamine-containing peptides exhibited scramblase activity in monomeric form, the polar glutamine residue would be exposed to the hydrocarbon region of the membrane, perturbing the membrane and promoting the lipid flip-flop. These scrambling peptides would be valuable tools to regulate lipid flip-flop in the plasma membrane.
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http://dx.doi.org/10.1063/4.0000045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980860PMC
March 2021

Impact of penile rehabilitation with phosphodiesterase-5 inhibitors on recovery of erectile function in patients undergoing robot-assisted radical prostatectomy: A propensity score-matched analysis.

Int J Urol 2021 Mar 4. Epub 2021 Mar 4.

Department of Urology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan.

Objective: To investigate the impact of penile rehabilitation on the recovery of erectile function after robot-assisted radical prostatectomy.

Methods: Patients who underwent robot-assisted radical prostatectomy in our department from 2010 to 2019 were included. For penile rehabilitation, a phosphodiesterase-5 inhibitor (tadalafil 20 mg) was administered twice a week for 1-6 months postoperatively. The International Index of Erectile Function questionnaire (question 1 and erectile function domain) and the Expanded Prostate Cancer Index Composite questionnaire (sexual function) were used.

Results: After propensity score matching, there were 79 patients in the penile rehabilitation group and 79 patients in the non-penile rehabilitation group. There was no significant difference in baseline characteristics between the two groups. Significantly higher scores were seen in the penile rehabilitation group compared with the non-penile rehabilitation group at postoperative 3, 6 and 9 months in the International Index of Erectile Function questionnaire-question 1, at 3, 6, 9 and 12 months in erectile function domain, and at 3, 6, 12 and 24 months in Expanded Prostate Cancer Index Composite questionnaire sexual function (P < 0.05). There were significant improvements in the erectile recovery rate in the penile rehabilitation group compared with the non-penile rehabilitation group in the nerve sparing (P = 0.006) and partial nerve sparing (P = 0.037) groups.

Conclusions: The present findings suggest that robot-assisted radical prostatectomy patients who undergo not only nerve sparing, but also those who undergo patial nerve sparing could benefit from penile rehabilitation using a phosphodiesterase-5 inhibitor.
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http://dx.doi.org/10.1111/iju.14527DOI Listing
March 2021

Extension of "Interfacial Adsorption Denaturation" Behavior Interpretation Based on Gibbs Monolayer Formation by Biomolecules.

J Oleo Sci 2021 ;70(3):349-362

Graduate School of Science and Engineering, Saitama University.

Using glucose oxidase and salmon testis-derived DNA molecules, we sought to extend the recently proposed idea of interfacial adsorption denaturation. The surface pressure-time (π-t) isotherm of the glucose oxidase Gibbs monolayer exhibited a rapid increase in surface pressure and a relatively prompt transition to a liquid condensed film. The appearance of this rapid liquid expansion phase occurred much earlier than that previously identified for lysozyme, trypsin, cytochrome C, and luciferase. This experimental finding was linked to the number of hydrophobic residues in the constituent unit, and the number of hydrophobic residues in glucose oxidase was the highest among these biomolecules. On the other hand, DNA molecules do not have such hydrophobic groups, or present a positive surface on the π-t curve. However, interfacial adsorption occurred, and the existence of molecules at the air/water interface was confirmed, even in the two-dimensional gas phase state. Furthermore, it was confirmed that an increase in surface pressure was detected during the formation of a mixed film of DNA molecules and biomolecules, forming a stable Gibbs monolayer. This mimic the behavior of mixed monolayer formation with matrix molecules in Langmuir monolayers. Moreover, it was clarified that the interfacial adsorption denaturation behavior changed when pH dependence was evaluated considering the isoelectric point of the biomolecular group.
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http://dx.doi.org/10.5650/jos.ess20222DOI Listing
January 2021

Low level of postoperative plasma antithrombin III is associated with portal vein thrombosis after liver surgery.

Surg Today 2021 Mar 3. Epub 2021 Mar 3.

Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Purpose: Although decreased antithrombin-III (AT-III) is a risk factor for portal vein thrombosis (PVT) in patients with liver cirrhosis, the association between postoperative PVT and postoperative AT-III levels is unknown in patients undergoing hepatectomy.

Methods: Patients who underwent hepatectomy between 2015 and 2018 were retrospectively analyzed. Postoperative PVT was assessed on CT at days 6-9 after hepatectomy. One-to-one propensity score (PS) matching was used to match the baseline characteristics.

Results: Of the 295 patients included in this analysis, 19 patients (6.4%) were diagnosed with postoperative PVT. The AT-III level on postoperative day (POD) 3 predicted postoperative PVT with a sensitivity/specificity of 74%/59% (AUC, 0.644; cut-off value, 60%; p = 0.032). Multivariate analysis revealed that AT-III levels ≤ 60% on POD3 (OR, 3.01; 95% CI 1.02-8.89; p = 0.046), cirrhosis (OR, 5.88; 95% CI 1.92-18.0; p = 0.002) and right-sided hepatectomy (OR, 4.16; 95% CI 1.45-11.9; p = 0.0079) were significant risk factors for postoperative PVT. After PS matching, 56 patients with and without AT-III supplementation were analyzed. The two groups had a similar incidence of PVT (p = 0.489).

Conclusions: Patients with AT-III levels ≤ 60% on POD3 should be carefully followed up regarding postoperative PVT. Our results did not support the efficacy of routine AT-III supplementation for the prophylaxis of postoperative PVT.
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http://dx.doi.org/10.1007/s00595-021-02257-xDOI Listing
March 2021

Accumulation of Macromolecules in Idiopathic Normal Pressure Hydrocephalus.

Neurol Med Chir (Tokyo) 2021 Mar 27;61(3):211-218. Epub 2021 Jan 27.

Department of Neurosurgery, Sapporo Medical University, Sapporo, Hokkaido, Japan.

The clearance system in the brain is not completely understood. The aim of this study was to prove the presence of the "glymphatic system" in the human brain using magnetic resonance spectroscopy (MRS).Spectral data of the brain white matter were obtained from healthy volunteers and patients with hydrocephalic dementia and used to measure intracerebral metabolites, including macromolecules (MMs) and lipids. Data were transferred from the MRS scanners to a workstation, and metabolites were quantified with the spectrogram-based eddy current method and water scaling.MM levels were significantly higher in patients with a slow gait and executive dysfunction due to normal pressure hydrocephalus (NPH) than in asymptomatic volunteers (p <0.01). In contrast, the N-acetyl aspartate (NAA) level was significantly lower in patients with executive dysfunction than in asymptomatic volunteers (p <0.01). There were no statistically significant differences in metabolites, including alanine, aspartate, creatine, γ-amino butyric acid, D-glucose, glutamine, glutamate, glycerophosphorylcholine, phosphorylcholine, lactate, myoinositol, N-acetyl-aspartyl-glutamate, scyllo-inositol, taurine, creatine methylene, and guanine, in the centrum semiovale between patients with NPH and asymptomatic volunteers.We quantitatively evaluated cerebral metabolites, particularly in the centrum semiovale, with MRS. In the brain of patients with a slow gait and executive dysfunction due to NPH, MRS revealed significantly higher MM levels and lower NAA levels compared to healthy volunteers. Therefore, it may be concluded that the patients have a dysfunctional glymphatic system in the brain.
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http://dx.doi.org/10.2176/nmc.oa.2020-0274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966205PMC
March 2021

Eye Movement Network Originating from Frontal Eye Field: Electric Cortical Stimulation and Diffusion Tensor Imaging.

Neurol Med Chir (Tokyo) 2021 Mar 28;61(3):219-227. Epub 2021 Jan 28.

Department of Neurosurgery, Sapporo Medical University, Sapporo, Hokkaido, Japan.

This study investigated the networks originating from frontal eye fields (FEFs) using electric cortical stimulation and diffusion tensor imaging (DTI). Seven patients with intractable focal epilepsy, in which FEFs were identified by electrical cortical stimulation, were enrolled in this study. Electric stimulation at 50 Hz was applied to the electrodes for functional mapping. DTI was used to identify the subcortical fibers originating from the FEFs with two regions of interests (ROIs) in the FEF and contralateral paramedian pontine reticular formation (PPRF). FEFs were found in the superior precentral sulcus (pre-CS) in six patients and superior frontal gyrus (SFG) in three patients. DTI detected fibers connecting FEFs and contralateral PPRFs, passing within the internal capsule. The fibers were located close to the lateral antero-superior border of the subthalamic nucleus (STN) and medial posterior border of the globus pallidus internus (GPi). This study found the characteristic subcortical networks of the FEF. These tracts should be noted to prevent complications of deep brain stimulation (DBS) of the STN or GPi.
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http://dx.doi.org/10.2176/nmc.oa.2020-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966202PMC
March 2021

Novel mouse model for cholestasis-induced liver fibrosis resolution by cholecystojejunostomy.

J Gastroenterol Hepatol 2021 Jan 15. Epub 2021 Jan 15.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background And Aim: Studies on the resolution of liver fibrosis are becoming more important in this era of etiologic eradication. In contrast to the extensive research on the recovery of liver fibrosis induced by hepatotoxic injuries, regression of cholestatic liver fibrosis has been insufficiently examined owing to the limited availability of animal models.

Methods: We examined our novel recanalization mice model of biliary obstruction, involving anastomosis between the gallbladder and jejunum (G-J anastomosis) by invagination. Transgenic mice expressing green fluorescent protein (GFP) under the collagen 1(α)1 promoter underwent G-J anastomosis 14 days after bile duct ligation (BDL) and were sacrificed 14 days later.

Results: Transaminase and total bilirubin levels decreased to almost normal values on day 14 after G-J anastomosis. G-J anastomosis resulted in dramatic reversal of liver fibrosis induced by BDL. Activated portal fibroblasts (PFs) double-positive for GFP and Thy-1 on immunofluorescence in the liver of BDL-injured mice became less noticeable following G-J anastomosis. Messenger RNA expression of markers for activated PFs in the liver was downregulated after anastomosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were induced by BDL. After anastomosis, expressions of MMP-3, 8 as well as hepatocyte growth factor were further upregulated, whereas those of TIMP-1 and TIMP-3 were markedly downregulated.

Conclusions: Our established G-J anastomosis model is associated with fibrosis resolution and reduced PF activation through reopening of bile duct obstruction and will be valuable for studying the recovery process of cholestatic liver fibrosis.
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http://dx.doi.org/10.1111/jgh.15406DOI Listing
January 2021

MRI findings of spring ligament injury: association with surgical findings and flatfoot deformity.

Acta Radiol Open 2020 Dec 14;9(12):2058460120980145. Epub 2020 Dec 14.

Department of Radiology, St. Marianna University School of Medicine, Kawasaki, Japan.

Background: Spring ligament injury is an important cause for flatfoot deformity; however, reliability of magnetic resonance imaging (MRI) findings of spring ligament injury is still ambiguous.

Purpose: To investigate the reliability of MRI findings for the diagnosis of spring ligament injury.

Material And Methods: Forty-three cases with spring ligament injury proven by surgery and 29 control cases were enrolled. The spring ligament complex was demonstrated on proton density-weighted images reconstructed from 3D-isotropic MRI data. The presence of waviness, discontinuity, and abnormally high signal intensity of the spring ligament complex was evaluated by two radiologists in cooperation. Also, injury of the posterior tibial tendon (PTT) on MRI and the lateral talo-1st metatarsal angles on weight-bearing X-rays were evaluated.

Results: Discontinuity and abnormally high signal intensity of the superomedial calcaneonavicular ligament (SmCNL) on MRI were more frequently observed in patients with spring ligament injury than in controls ( < 0.001). Discontinuity and abnormally high signal intensity of the SmCNL were found more often in the PTT injury group than in those without ( < 0.001). The talo-1st metatarsal angle was greater in patients with discontinuity and abnormally high signal intensity of the SmCNL on MRI than in patients without these findings ( < 0.001).

Conclusion: Discontinuity and abnormally high signal intensity are reliable MRI findings for spring ligament injury and related disorders, such as flatfoot deformity and PTT injury.
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http://dx.doi.org/10.1177/2058460120980145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739123PMC
December 2020

Stroke Mimics and Chameleons from the Radiological Viewpoint of Glioma Diagnosis.

Neurol Med Chir (Tokyo) 2021 Feb 29;61(2):134-143. Epub 2020 Dec 29.

Department of Neurosurgery, Sapporo Medical University, Sapporo, Hokkaido, Japan.

Gliomas are sometimes difficult to differentiate from strokes and are often misdiagnosed on magnetic resonance imaging (MRI); thus, the terms "stroke mimics" and "stroke chameleons" have been introduced. In this study, we analyzed stroke mimics and stroke chameleons in glioma and discussed the diagnostic perplexity.We retrospectively reviewed cases that were removed from lesions that were considered to be brain tumors. This study enrolled 214 patients who underwent tumor resection for suspected glioma. Clinical characteristics and radiological findings of the patients were compared between the masquerade findings group, which was further divided into two groups: the stroke chameleons and stroke mimics according to their final diagnosis, and the intelligible findings group.Stroke chameleons and stroke mimics were significantly higher in age and smaller in lesion size than the intelligible findings group. In the multivariate analysis, the predictive factor of the masquerade finding group was higher age and smaller size. Stroke mimics group has a tendency to be higher rate of hyperintensity lesion on diffusion-weighted imaging (DWI) compared with stroke chameleons group. The average period from initial diagnosis to pathological diagnosis was 13.50 days in the stroke chameleons and 61.50 days in the stroke mimics, which proved significantly different.Proper diagnosis of glioma and stroke affects a patient's prognosis, and should be diagnosed as soon as possible. However, stroke mimics and stroke chameleons caused by glioma can occur. Thus, the diagnosis of a stroke should take into consideration the possibility of a glioma in real clinical situations.
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http://dx.doi.org/10.2176/nmc.oa.2020-0309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905296PMC
February 2021

COVID-19 infection in Hokkaido, Japan might depend on the viscosity of atmospheric air.

Virus Res 2021 02 10;293:198259. Epub 2020 Dec 10.

Department of Neurosurgery, Sapporo Medical University, Japan.

Background: The large number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has plunged the world into fear in recent times. In Japan, 18,769 novel coronavirus disease 2019 (COVID-19) cases have been reported as of June 30, 2020. This study aimed to assess whether cluster infection prevention is possible by evaluating the association between viral transmission and meteorological factors.

Methods: This study included 1263 people who were successively diagnosed with COVID-19 in Hokkaido, Japan between January 24, 2020 and June 30, 2020. After obtaining the values from the Japanese Meteorological Agency, the average scores of air temperature and humidity were calculated and compared with COVID-19 reproduction numbers, and the association between COVID-19 incidence or reproduction number and meteorological factors was assessed.

Results: The COVID-19 reproduction number in Hokkaido had three peaks that came several days before the surge in COVID-19 cases. The peaks are indicative of cluster infections. There was a strong negative correlation between the kinematic viscosity of atmospheric air and the reproduction number.

Discussion And Conclusion: Analysis of the reproduction number is important for predicting or suppressing COVID-19 infection clusters. The authors found a strong association between meteorological factors, such as kinematic viscosity of atmospheric air and the incidence of COVID-19 infection. Meteorological forecasts could provide foreknowledge about COVID-19 infection clusters in the future.
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http://dx.doi.org/10.1016/j.virusres.2020.198259DOI Listing
February 2021

Pathological Features of Persistent Atrial Standstill Syndrome in Three Dogs.

J Comp Pathol 2020 Oct 9;180:9-15. Epub 2020 Sep 9.

Laboratory of Veterinary Clinical Oncology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan. Electronic address:

The hearts of three dogs, clinically diagnosed as having persistent atrial standstill syndrome (PAS), were studied post mortem. The most significant gross findings in the hearts of all three dogs were dilatation and marked reduction in the thickness of both atrial walls. Histopathologically, all three had widespread progressive loss of the atrial myocardium with replacement by fatty or fibrofatty tissue, consistent with atrial myopathy. The lesion mainly affected the upper half of both atria and was more severe in the epimyocardium and midmyocardium than in the endomyocardium. On the basis of these observations, it is proposed that the atrial myopathy commences in the upper regions of both atria and progresses downwards, as has been demonstrated electrophysiologically in PAS in humans, and extends from the epicardium towards the endocardium.
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http://dx.doi.org/10.1016/j.jcpa.2020.08.005DOI Listing
October 2020

Preoperative Prediction of Communication Difficulties during Awake Craniotomy in Glioma Patients: A Retrospective Evaluation of 136 Cases at a Single Institution.

Neurol Med Chir (Tokyo) 2021 Jan 19;61(1):21-32. Epub 2020 Nov 19.

Department of Neurosurgery, Sapporo Medical University.

Awake craniotomy has been widely performed in patients with glioma in eloquent areas to minimize postoperative brain dysfunction. However, neurological examination in awake craniotomy is sometimes problematic due to communication difficulties during the intraoperative awake period. We evaluated preoperative predictors of these difficulties in awake craniotomy for patients with glioma. In all, 136 patients with glioma who underwent awake craniotomy at our institution between January 2012 and January 2020 were retrospectively evaluated. Patients were divided into two groups (appropriately awake group and inappropriately awake group) depending on their state during the intraoperative awake period, and the relationship between communication difficulties in awake craniotomy and both clinical and radiological characteristics were assessed. The appropriately awake group included 110 patients, and the inappropriately awake group included 26 patients. Reasons for inclusion in the inappropriately awake group were insufficient wakefulness in 15 patients, restless state in 6, and intraoperative seizures in 5. In multivariate analysis, the likelihood of being inappropriately awake was inversely correlated with preoperative seizures (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.06-0.89; p = 0.033) and positively correlated with left-sided lesions (OR, 7.31; 95% CI, 1.54-34.62; p = 0.012). Both lack of preoperative seizures and left-sided lesions were identified as risk factors for intraoperative difficulties in awake craniotomy for patients with glioma. Understanding these risk factors may lead to more appropriate determination of eligibility for awake craniotomy.
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http://dx.doi.org/10.2176/nmc.oa.2020-0232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812311PMC
January 2021

Preoperatively estimated graft flow rate contributes to the improvement of hemodynamics in revascularization for Moyamoya disease.

J Stroke Cerebrovasc Dis 2021 Jan 7;30(1):105450. Epub 2020 Nov 7.

Department of Neurosurgery, Sapporo Medical University, Sapporo, Hokkaido, Japan.

Objectives: Superficial temporal artery (STA)-middle cerebral artery (MCA) bypass operation is an effective treatment for patients with Moyamoya disease, and the hemodynamic parameters are reported to be improved after operation. However, there is no report concerning hemodynamic changes from the viewpoint of the preoperative anatomical structure of grafts. In this study, we evaluated the correlation between the preoperatively estimated blood flow of the graft obtained through image-based computational fluid dynamics (CFD) analysis and the hemodynamic changes in the acute phase after revascularization.

Materials And Methods: A total of 30 hemispheric sides of 23 patients were examined. The blood flow, that is, flow rate (FR) of the STA branches that were anastomosed to the MCA was evaluated using CFD analysis based on computed tomography (CT) angiography imaging data. The correlations between the FR and the hemodynamic changes in the acute phase after revascularization obtained through CT perfusion were assessed.

Results: The preoperatively estimated FR of the graft was moderately correlated with the changes in the mean transit time significantly and weakly correlated with those in the cerebral blood flow and cerebral blood volume. In addition, the FR was strongly correlated with age and the diameter of the STA from the origin to the bifurcation.

Conclusion: The preoperatively estimated FR of the graft obtained through image-based CFD analysis contributed to the improvement of the mean transit time after revascularization. Because the FR of the graft was associated with the diameter of the STA, the size of the STA might be an important factor in postoperative hemodynamic changes. This might lead to the risk assessment of acute drastic hemodynamic changes as cerebral hyperperfusion, and consequently, better surgical outcomes might be expected.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105450DOI Listing
January 2021

Pretransplantation splenomegaly frequently persists after liver transplantation and can manifest as hypersplenism and graft fibrosis - a retrospective study.

Transpl Int 2020 12 9;33(12):1807-1820. Epub 2020 Nov 9.

Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The risk factors and clinical impact of post-transplantation splenomegaly (SM) are poorly understood. We investigated the predictors and impacts of post-transplantation SM in 415 LT patients at Kyoto University Hospital from April 2006 to December 2015. First, the predictors and clinical consequences of SM three years post-transplantation were analyzed among spleen-preserved recipients. Second, the clinical data of surviving recipients three years post-transplantation were compared between splenectomized and spleen-preserved recipients. There was no difference in indication for liver transplantation between these two groups. Third, survival outcomes were compared between splenectomized and spleen-preserved recipients. SM was determined as a SV/body surface area (BSA) higher than 152 ml/m . In the first analysis, preoperative SM occurred in 79.9% recipients and SM persisted three years post-transplantation in 72.6% recipients among them. Preoperative SV/BSA was the only independent predictor of three year post-transplantation SM, which was associated with lower platelet (PLT), white blood cell (WBC) counts and significant graft fibrosis (21.4% vs. 2.8%). In the second analysis, spleen-preservation was related to lower PLT, WBC counts and a higher proportion of significant graft fibrosis (26.7% vs. 7.1%) three years post-transplantation. In the third analysis, spleen-preserved recipients showed worse survival than splenectomized recipients. In conclusion, preoperative SM frequently persists more than three years post-transplantation and is associated with subclinical hypersplenism, graft fibrosis, graft loss, and even death.
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http://dx.doi.org/10.1111/tri.13761DOI Listing
December 2020

Effects of nerve-sparing procedures on bowel function after robot-assisted radical prostatectomy: A longitudinal study.

Int J Med Robot 2020 Dec 8;16(6):1-10. Epub 2020 Oct 8.

Division of Urology, Tottori University Faculty of Medicine, Tottori, Japan.

Background: This study aimed to evaluate rectal pain and bowel function of the patients following robot-assisted radical prostatectomy (RARP).

Methods: We divided 296 patients who underwent RARP into two groups depending on the intervention: NS (nerve-sparing) group (bilateral NS, unilateral NS and bilateral partial NS) and non-NS group (unilateral partial NS, bilateral non-NS). Bowel function was assessed using the Extended Prostate Cancer Index Composite for 24 months after RARP.

Results: The bowel function score and rectal urgency at 1-6 months after RARP were more significantly impaired in the non-NS group than in the NS group (p < 0.05). In a multivariate analysis of factors affecting the bowel function score at 6 months after RARP, only NS procedure had a significant effect.

Conclusions: In the initial period after RARP, bowel symptoms were significantly impaired. This impairment was affected by the degree of NS. These results could guide patients in their decision to choose RARP.
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http://dx.doi.org/10.1002/rcs.2156DOI Listing
December 2020

Utility of Mac-2 Binding Protein Glycosylation Isomer to Evaluate Graft Status After Liver Transplantation.

Liver Transpl 2021 02 1;27(3):403-415. Epub 2020 Oct 1.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan.

Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel liver fibrosis biomarker, but there are few studies on M2BPGi in liver transplantation (LT) recipients. This study aimed to evaluate the utility of M2BPGi measurement in LT recipients. We collected the clinicopathological data of 233 patients who underwent a liver biopsy at Kyoto University Hospital after LT between August 2015 and June 2019. The median values of M2BPGi in patients with METAVIR fibrosis stages F0, F1, F2, and ≥F3 were 0.61, 0.76, 1.16, and 1.47, respectively, whereas those in patients with METAVIR necroinflammatory indexes A0, A1, and ≥A2 were 0.53, 1.145, and 2.24, respectively. Spearman rank correlation test suggested that the necroinflammatory index had a stronger correlation to the M2BPGi value than the fibrosis stage. The area under the receiver operating characteristic curve of M2BPGi to predict ≥A1 was 0.75, which was significantly higher than that of any other liver fibrosis and inflammation marker. Patients with a rejection activity index (RAI) of ≥3 had a higher M2BPGi value than those with RAI ≤ 2 (P = 0.001). Patients with hepatitis C virus viremia had a higher M2BPGi value than sustained virological responders or those with other etiologies. In conclusion, the present study demonstrated that M2BPGi values are more strongly influenced by necroinflammatory activity and revealed M2BPGi, which has been thought to be a so-called fibrosis marker, as a disease activity marker in transplant recipients. M2BPGi measurement may be useful to detect early stage liver inflammation that cannot be detected by routine blood examination of LT recipients.
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http://dx.doi.org/10.1002/lt.25870DOI Listing
February 2021

A case of primary hepatic mixed neuroendocrine-non-neuroendocrine tumor (MiNEN) associated with gallbladder carcinosarcoma.

Clin J Gastroenterol 2020 Dec 10;13(6):1280-1288. Epub 2020 Aug 10.

Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

A woman in her seventies visited our hospital because of abdominal pain. Multiple hepatic tumors were detected and a liver biopsy revealed mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), which was composed of cholangiocellular carcinoma and neuroendocrine tumor (NET). Diagnostic imaging ruled out primary malignancies other than the liver and identified that the tumor originated from the liver. Because a predominant and aggressive part of the tumor was considered to be cholangiocellular carcinoma, gemcitabine and S-1 were used as first-line treatment. After the treatment, octreotide acetate was administered for the NET component, followed by transcatheter arterial embolization. Subsequently, her gallbladder (GB) rapidly swelled with biliary tract obstruction, and cholecystectomy revealed carcinosarcoma of the GB. She is still undergoing treatment at 44 months after diagnosis. Herein we report this case of primary hepatic MiNEN consisting of cholangiocarcinoma and NET, followed by GB carcinosarcoma. This is the first case illustrating that a multidisciplinary treatment approach for MiNEN accompanied with carcinosarcoma, involving assessment and treatment targeting the most aggressive component, can result in a long survival time.
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http://dx.doi.org/10.1007/s12328-020-01202-8DOI Listing
December 2020

Esophageal carcinosarcoma in which the sarcomatous element has sloughed off: A case report.

Int J Surg Case Rep 2020 3;74:27-31. Epub 2020 Aug 3.

Department of Surgery, Iwate Medical University School of Medicine, 2-1-1 Idaidori, Yahaba, Iwate 028-3695, Japan.

Introduction: Most esophageal carcinosarcoma (ECS) tumors present as a polypoid tumor that is continuous with the superficial lesion and suspended by a pedicle. Here, we report a case of ECS in which a polypoid lesion sloughed off before surgery.

Presentation Of Case: A 76-year-old man with dysphagia was admitted to our hospital. Esophagogastroscopy revealed a 20-mm polypoid tumor continuous with a superficial lesion and attached to the lesion by a thin pedicle in the mid-thoracic esophagus. Histopathological examination of the endoscopic biopsy showed that the superficial lesion was a moderately differentiated squamous cell carcinoma and that the polypoid tumor contained a sarcomatous element. He was diagnosed with ECS and underwent radical esophagectomy with three-field lymph node dissection. In the resected specimen, no polypoid tumor was found, and only a superficial lesion was observed. The histopathological findings revealed only squamous cell carcinoma, and the pathological diagnosis was esophageal squamous cell carcinoma, pT1bN0M0, pathological stage I. The patient was discharged from the hospital 22 days after surgery and did not experience any complications. He is currently alive and remained cancer-free for three years since surgery was performed.

Discussion: Due to the distinctive configuration in which the polypoid lesion was connected to the superficial cancerous lesion by a very thin pedicle, researchers suggested that the polypoid tumor, which consisted of a sarcomatous element, was sloughed off before surgery.

Conclusion: We encountered a rare case of ECS in which the sarcomatous element sloughed off prior to surgical resection.
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http://dx.doi.org/10.1016/j.ijscr.2020.07.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415637PMC
August 2020

The Prognosis of Hepatocellular Carcinoma Treated with Sorafenib in Combination with TACE.

Asian Pac J Cancer Prev 2020 Jun 1;21(6):1797-1805. Epub 2020 Jun 1.

Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541 Japan.

Objective: Sorafenib have been shown to be effective in the treatment of advanced HCC and has been standard therapy since its release in Japan in 2009 (Llovet et al., 2008; Cheng et al., 2009). However, due to a low response rate, more aggressive combination treatment has been utilized as a multimodal strategy. The present study aimed to determine the efficacy of sorafenib alone and in combination with transarterial chemoembolization (TACE) for the treatment of advanced HCC.

Methods: All patients with unresectable advanced HCC who were prescribed sorafenib at Kanto Rosai Hospital were included in the study. Five-year overall survival (OS) rates were estimated for patients treated with sorafenib alone or in combination with TACE. Multivariate and univariate regression analyses were performed to identify factors affecting OS. Analysis using propensity score matching and inverse-probability weights were also performed.

Results: A total of 46 patients were treated with sorafenib up to June 2018. The total sorafenib dose administered was higher in the TACE combination group (70900 mg vs. 24000 mg vs. with sorafenib alone), although the relative dose intensity was lower (11.7% vs. 17.6%, respectively). The 5-year survival prognosis estimated using the Kaplan-Meier method was longer in patients treated with sorafenib in combination with TACE versus sorafenib alone (36.3% vs. 7.7%). Combination with TACE was the only factor associated with improved OS in both univariate and multivariate analysis. Among cases matched by propensity scores the hazard rate for combination with TACE was 0.067 (95% CI 0.091-1.128).

Conclusion: With an array of therapeutic options currently available, it is important to determine the efficacy of different multimodal strategies, such as sorafenib combined TACE, for patients with unresectable HCC.
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http://dx.doi.org/10.31557/APJCP.2020.21.6.1797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568902PMC
June 2020

USP42 enhances homologous recombination repair by promoting R-loop resolution with a DNA-RNA helicase DHX9.

Oncogenesis 2020 Jun 15;9(6):60. Epub 2020 Jun 15.

Department of Biomedical Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan.

The nucleus of mammalian cells is compartmentalized by nuclear bodies such as nuclear speckles, however, involvement of nuclear bodies, especially nuclear speckles, in DNA repair has not been actively investigated. Here, our focused screen for nuclear speckle factors involved in homologous recombination (HR), which is a faithful DNA double-strand break (DSB) repair mechanism, identified transcription-related nuclear speckle factors as potential HR regulators. Among the top hits, we provide evidence showing that USP42, which is a hitherto unidentified nuclear speckles protein, promotes HR by facilitating BRCA1 recruitment to DSB sites and DNA-end resection. We further showed that USP42 localization to nuclear speckles is required for efficient HR. Furthermore, we established that USP42 interacts with DHX9, which possesses DNA-RNA helicase activity, and is required for efficient resolution of DSB-induced R-loop. In conclusion, our data propose a model in which USP42 facilitates BRCA1 loading to DSB sites, resolution of DSB-induced R-loop and preferential DSB repair by HR, indicating the importance of nuclear speckle-mediated regulation of DSB repair.
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http://dx.doi.org/10.1038/s41389-020-00244-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296013PMC
June 2020

Recurrence Interval Within 1 Year Leads to Death in Patients with Grade 2 Meningioma.

World Neurosurg 2020 10 23;142:e58-e65. Epub 2020 May 23.

Department of Neurosurgery, Sapporo Medical University, Sapporo, Hokkaido, Japan.

Objective: Grade 2 meningioma is more likely to recur than grade 1 meningioma. Recurrence decreases overall survival in patients with grade 2 meningioma. However, the clinical course of grade 2 meningioma with several repeated recurrences is poorly understood. The purpose of this study was to clarify the clinical characteristics of grade 2 meningioma with repeated recurrences.

Methods: This study included 28 patients with grade 2 meningioma treated at our institution from January 1994 to December 2017. The relationship between survival and factors including age, sex, number of recurrences, malignant transformation, radiation therapy, tumor location, MIB-1 labeling index, Simpson grade, Karnofsky Performance Status, and surgical interval were analyzed.

Results: The average age at the initial operation was 53.4 years. The number of recurrences was 3.7 times on average during the follow-up of 113.9 months after the initial operation. An increasing number of recurrences resulted in shortening of the surgical interval, increase in the MIB-1 labeling index, and decrease in Karnofsky Performance Status. In fatal cases, the average surgical interval before death was approximately 1 year. Three factors were related to poor prognosis: number of recurrences (odds ratio, 1.620; P = 0.030), malignant transformation (odds ratio, 10.625; P = 0.019), and high MIB-1 labeling index (odds ratio, 1.089; P = 0.044).

Conclusions: Shortening of the surgical interval within 1 year because of multiple recurrences led to death in patients with grade 2 meningioma. Malignant transformation was the most potent among the poor prognostic factors.
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http://dx.doi.org/10.1016/j.wneu.2020.05.145DOI Listing
October 2020

Natural Y-shaped radial artery graft bypass for a complex middle cerebral artery aneurysm: A case report.

J Stroke Cerebrovasc Dis 2020 Jul 8;29(7):104853. Epub 2020 May 8.

Department of Neurosurgery, Sapporo Medical University, South 1 West 16, Chuo-ku, Sapporo 060-8543, Japan. Electronic address:

Giant thrombosed middle cerebral artery (MCA) aneurysms are difficult to treat and sometimes require complex revascularization using allografts. We describe a technical method using revascularization with a natural Y-shaped graft that provides a normal variation for a complex MCA aneurysm. A 65-year-old man with a giant thrombosed MCA aneurysm presented with right hemiparesis and aphasia. The patient had a history of clipping surgery for the ipsilateral side of the MCA aneurysm 25 years before, and a de novo aneurysm developed over the previous 18 years. For the giant thrombosed aneurysm, trapping and revascularization were performed. A natural radial artery Y-graft was used as the graft and anastomosed to both M2 trunks. The symptoms improved after surgery, and the patient was discharged 3 weeks later. This is the first report of a double-barrel bypass using a natural Y-graft. This method attained a normal variation, and the flow of the Y-graft was physiological. For the radical cure of giant thrombosed MCA aneurysms, multiple revascularizations might be required. With this natural Y-graft, complex transpositions could be avoided.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104853DOI Listing
July 2020

Extent of liver resection is associated with incomplete liver restoration and splenomegaly a long period after liver resection.

Surgery 2020 07 27;168(1):40-48. Epub 2020 Apr 27.

Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Japan.

Background: Little is known about the clinical significance and risk factors for incomplete liver restoration after partial hepatectomy, which is defined by a liver volume restoration of less than 100% of the original volume.

Methods: We retrospectively analyzed patients who underwent hepatic resection for liver tumors at the Kyoto University Hospital between January 2011 and October 2015 and survived without recurrence for more than 3 years. The preoperative and postoperative data, as well as liver and splenic volume after 3 postoperative years, were assessed.

Results: The percentage of resected liver was higher in the incomplete liver restoration group (n = 52, 41.6%) than in the complete liver restoration group (n = 73, 58.4%) (28 [3-78]% vs 14.5 [2-63]%, P = .0226). The percentage of resected liver was also higher in the splenomegaly group (defined by spleen volume increases of more than 35% of the original volume) than in the nonsplenomegaly group (40 [4-63]% vs 16.5 [2-78]%, P = .0002). Multivariate analysis demonstrated that the percentage of resected liver was a significant predictor of incomplete liver restoration (odds ratio = 9.75, P = .0043) and splenomegaly (odds ratio = 74.4, P = .0006). Incomplete liver restoration 3 years after hepatectomy was associated with lower serum albumin levels (4.0 [2.4-4.7] g/dL compared with 4.2 [2.6-4.8] g/dL in the complete liver restoration group, P = .0032). Splenomegaly was associated with a lower platelet count (109.9 ± 49.8 x10/μL vs 163 ± 58.1 × 10/μLP = .0007) and lower serum albumin level (3.6 [2.6-4.4] g/dL vs 4.1 [2.4-4.8] g/dL, P = .0002).

Conclusion: An extensive resection of the liver parenchyma results in an increased risk for incomplete liver restoration and splenomegaly long after hepatectomy, which is associated with the clinical consequences of hypoalbuminemia and thrombocytopenia.
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http://dx.doi.org/10.1016/j.surg.2020.02.022DOI Listing
July 2020

Small-volume lymph node involvement and biochemical recurrence after robot-assisted radical prostatectomy with extended lymph node dissection in prostate cancer.

Int J Clin Oncol 2020 Jul 24;25(7):1398-1404. Epub 2020 Apr 24.

Division of Urology, Department of Surgery, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.

Background: We investigated prognostic factors for biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP) with extended pelvic lymph node (LN) dissection.

Methods: We included 173 patients who underwent RARP with extended pelvic LN dissection without neoadjuvant therapy at our hospital between October 2010 and April 2018. BCR was defined as prostate serum antigen (PSA) levels ≥ 0.2 ng/mL; BCR-free survival rates were determined using Kaplan-Meier analysis. We used Cox regression analysis to evaluate effects of PSA and pathologic variables on BCR.

Results: Median follow-up was 27.9 (range 6.1-86.9) months. Five-year BCR-free survival was 89.5%. In multivariate analysis, positive LNs (HR 7.117; 95% CI 2.826-17.925; P < 0.001) and Gleason score (GS) ≥ 8 (HR 2.612; 95% CI 1.051-6.489; P = 0.039) were significant predictors of BCR. Patients with 1 or 2 positive LNs (n = 10) had significantly higher BCR-free survival rates than patients with ≥ 3 positive LNs (n = 5). We, therefore, stratified the patients as low-risk (GS < 8 and no positive LNs), intermediate-risk: (either GS ≥ 8 or positive LNs) and high-risk (both GS ≥ 8 and positive LNs). Their 1-year BCR-free survival rates were low-risk: 94.6%, intermediate-risk: 88.5%, and high-risk: 33.3% (P < 0.05).

Conclusions: Patients with 1-2 positive LNs and GS < 8 have low risk for BCR; close observation without immediate adjuvant hormonal therapy can be considered for these patients.
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http://dx.doi.org/10.1007/s10147-020-01682-1DOI Listing
July 2020

Ischemic Tolerance Evaluated by Computed Tomography Perfusion during Balloon Test Occlusion.

J Stroke Cerebrovasc Dis 2020 Jun 13;29(6):104807. Epub 2020 Apr 13.

Division of Radiology, Sapporo Medical University Hospital, Sapporo, Japan.

Objectives: Balloon test occlusion (BTO) is performed to evaluate ischemic tolerance for large and giant cerebral aneurysms and head and neck tumors that may require parent artery occlusion. However, ischemic tolerance for the temporary test occlusion does not always guarantee a tolerance for permanent occlusion. In this study, we evaluated the utility of computed tomography (CT) perfusion during BTO to quantify ischemic tolerance for detecting delayed ischemic stroke.

Materials And Methods: Forty-one patients who underwent BTO for the internal carotid artery were included. The correlations between the parameters of CT perfusion and collateral angiographic appearance or stump pressure during BTO were evaluated. The cerebral blood flow (CBF), cerebral blood volume, mean transit time (MTT), and time to peak (TTP) were obtained through CT perfusion, and the asymmetry ratios were determined. Collateral angiographic appearances were categorized into 5 grades (0-4).

Results: The collateral angiographic appearance showed moderate correlations with CBF, MTT, and TTP that was significant. Of these, the absolute value of the correlation coefficient was the highest for MTT. MTT also showed a moderate correlation with stump pressure. CBF and MTT were significantly different between the poor collateral group (grades 2 and 3) and the good collateral group (grade 4). Based on the MTT, the good collateral group was identified with high sensitivity (75.0%) and specificity (81.2%).

Conclusions: In BTO, the MTT obtained through CT perfusion showed a correlation with collateral angiographic appearance and stump pressure. Thus, the MTT might be useful to quantify ischemic tolerance for detecting delayed ischemic stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104807DOI Listing
June 2020

Health Related Quality of Life in Japanese Patients with Localized Prostate Cancer: Comparative Retrospective Study of Robot-Assisted Laparoscopic Radical Prostatectomy Versus Radiation Therapy.

Yonago Acta Med 2020 Feb 30;63(1):55-62. Epub 2020 Jan 30.

Division of Urology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.

Background: Radical prostatectomy and radiotherapy are standard treatments for localized prostate cancer. When making decisions about treatment, it is important to not only consider medical information such as the patient's age, performance status, and complications, but also the impact on quality of life (QOL) after treatment.

Our purpose was to compare health related quality of life (HRQOL) after robot-assisted laparoscopic radical prostatectomy (RARP) versus radiation therapy in Japanese patients with localized prostate cancer retrospectively.

Methods: Patients with localized prostate cancer receiving RARP or radiotherapy at Tottori University Hospital between October 2010 and December 2014 were enrolled in a retrospective observational study with follow-up for 24 months to December 2016. The Medical Outcome Study 8-Item Short-Form Health Survey was performed before treatment and 1, 3, 6, 12, and 24 months post-treatment.

Results: Complete responses to the questionnaire were obtained from 154/227 patients receiving RARP, 41/67 patients receiving intensity-modulated radiation therapy, 35/82 patients receiving low dose rate brachytherapy, and 18/28 patients given low dose rate brachytherapy plus external beam radiation therapy. The median physical component summary score of the Medical Outcome Study 8-Item Short-Form Health Survey was significantly lower at 1 month after prostatectomy than radiotherapy, but was similar for both treatments at 3 months, and was significantly higher at 6, 12 and 24 months after prostatectomy. The median mental component summary score was also significantly lower in the prostatectomy group at 1 month, but not from 3 months onwards.

Conclusion: Our study suggested that HRQOL was inferior at 1 month after RARP, however, recovered at 3 months after RARP and was better than after radiotherapy at 6, 12, and 24 months.
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http://dx.doi.org/10.33160/yam.2020.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028529PMC
February 2020

Gpr120 mRNA expression in gonadotropes in the mouse pituitary gland is regulated by free fatty acids.

J Reprod Dev 2020 Jun 28;66(3):249-254. Epub 2020 Feb 28.

Laboratory of Environmental Physiology, Department of Life Science, School of Science and Engineering, Kindai University, Higashiosaka 577-8502, Japan.

GPR120 is a long-chain fatty acid (LCFA) receptor that is specifically expressed in gonadotropes in the anterior pituitary gland in mice. The aim of this study was to investigate whether GPR120 is activated by free fatty acids in the pituitary of mice and mouse immortalized gonadotrope LβT2 cells. First, the effects of palmitate on GPR120, gonadotropic hormone b-subunits, and GnRH-receptor expression in gonadotropes were investigated in vitro. We observed palmitate-induced an increase in Gpr120 mRNA expression and a decrease in follicle-stimulating hormone b-subunit (Fshb) expression in LβT2 cells. Furthermore, palmitate exposure caused the phosphorylation of ERK1/2 in LβT2 cells, but no significant changes were observed in the expression levels of luteinizing hormone b-subunit (Lhb) and gonadotropin releasing hormone-receptor (Gnrh-r) mRNA and number of GPR120 immunoreactive cells. Next, diurnal variation in Gpr120 mRNA expression in the male mouse pituitary gland was investigated using ad libitum and night-time restricted feeding (active phase from 1900 to 0700 h) treatments. In ad libitum feeding group mice, Gpr120 mRNA expression at 1700 h was transiently higher than that measured at other times, and the peak blood non-esterified fatty acid (NEFA) levels were observed from 1300 to 1500 h. These results were not observed in night-time-restricted feeding group mice. These results suggest that GPR120 is activated by LCFAs to regulate follicle stimulating hormone (FSH) synthesis in the mouse gonadotropes.
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http://dx.doi.org/10.1262/jrd.2019-166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297631PMC
June 2020

Metabolic-Pathway-Oriented Screening Targeting -Adenosyl-l-methionine Reveals the Epigenetic Remodeling Activities of Naturally Occurring Catechols.

J Am Chem Soc 2020 01 23;142(1):21-26. Epub 2019 Dec 23.

Core Research for Evolutional Science and Technology (CREST) , Japan Agency for Medical Research and Development (AMED) , 1-7-1 Otemachi , Chiyoda-ku , Tokyo 100-0004 , Japan.

Methyl transfer reactions play important roles in many biological phenomena, wherein the methylation cofactor -adenosyl-l-methionine (SAM) serves as the important currency to orchestrate those reactions. We have developed a fluorescent-probe-based high-throughput screening (HTS) system to search for the compounds that control cellular SAM levels. HTS with a drug repositioning library revealed the importance of catechol--methyltransferase (COMT) and its substrates in controlling the SAM concentrations and histone methylation levels in colorectal tumor cells.
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http://dx.doi.org/10.1021/jacs.9b08698DOI Listing
January 2020